The overall hypothesis of this project is that immuno-gene therapy can be used successfully to treat malignant pleural mesothelioma (MPM). The Project will continue to move the preclinical findings from Projects 2 and 3 into cutting-edge clinical trials (bench-to-bedside); and to provide clinical data and specimens back to Projects 2 and 3 to inform improvements in the next iteration of clinical trials (bedside-to bench). The first focus of this project is to continue and extend successful trials using intrapleural injections of an adenovirus (Ad) expressing type 1 interferon (Ad.lFN). Based on preclinical data from Project 2, a Phase 1/2 trial was initiated combining two Ad.IFN-alpha doses (given 3 days apart) with concomitant Celecoxib administration, followed two weeks later by 4-6 cycles of either front-line (pemetrexed/cisplatin/) or second-line (gemcitabine/carboplatin) chemotherapy. Aim 1 of this proposal is to complete the Phase 2 trial to determine if the response rate warrants moving this therapy to a larger randomized Phase 2 or 3 trial by either industry or cooperative groups. The second focus of the Project is adoptive T cell therapy using T cells with chimeric antigen receptors (CARs) initially targeted to the mesothelioma tumor surface antigen, mesothelin. Given potential safety concerns with some other CARs, a trial using T-cells transduced with GMP grade mRNA will be conducted (Aim 2A). Since CAR expression time is limited, if any